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New Class of Selective Estrogen Receptor Degraders (SERDs): Expanding the Toolbox of PROTAC Degrons.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-07-05 , DOI: 10.1021/acsmedchemlett.8b00106 Lucia Wang 1 , Valeria S Guillen 2 , Naina Sharma 2 , Kevin Flessa 1 , Jian Min 2 , Kathryn E Carlson 2 , Weiyi Toy 3 , Sara Braqi 1 , Benita S Katzenellenbogen 2 , John A Katzenellenbogen 2 , Sarat Chandarlapaty 3 , Abhishek Sharma 1
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-07-05 , DOI: 10.1021/acsmedchemlett.8b00106 Lucia Wang 1 , Valeria S Guillen 2 , Naina Sharma 2 , Kevin Flessa 1 , Jian Min 2 , Kathryn E Carlson 2 , Weiyi Toy 3 , Sara Braqi 1 , Benita S Katzenellenbogen 2 , John A Katzenellenbogen 2 , Sarat Chandarlapaty 3 , Abhishek Sharma 1
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An effective endocrine therapy for breast cancer is to selectively and effectively degrade the estrogen receptor (ER). Up until now, there have been largely only two molecular scaffolds capable of doing this. In this study, we have developed new classes of scaffolds that possess selective estrogen receptor degrader (SERD) and ER antagonistic properties. These novel SERDs potently inhibit MCF-7 breast cancer cell proliferation and the expression of ER target genes, and their efficacy is comparable to Fulvestrant. Unlike Fulvestrant, the modular protein-targeted chimera (PROTAC)-type design of these novel SERDs should allow easy diversification into a library of analogs to further fine-tune their pharmacokinetic properties including oral availability. This work also expands the pool of currently available PROTAC-type scaffolds that could be beneficial for targeted degradation of various other therapeutically important proteins.
中文翻译：
新型的选择性雌激素受体降解剂（SERD）：扩展PROTAC污垢的工具箱。
乳腺癌的有效内分泌治疗是选择性和有效降解雌激素受体（ER）。迄今为止，基本上只有两种分子支架能够做到这一点。在这项研究中，我们已经开发出具有选择性雌激素受体降解剂（SERD）和ER拮抗特性的新型支架。这些新颖的SERD可以有效抑制MCF-7乳腺癌细胞的增殖和ER靶基因的表达，其功效与Fulvestrant相当。与Fulvestrant不同的是，这些新型SERD的模块化蛋白靶向嵌合体（PROTAC）型设计应易于分散到类似物库中，以进一步微调其药代动力学特性，包括口服有效性。
更新日期：2018-07-05
中文翻译：
新型的选择性雌激素受体降解剂（SERD）：扩展PROTAC污垢的工具箱。
乳腺癌的有效内分泌治疗是选择性和有效降解雌激素受体（ER）。迄今为止，基本上只有两种分子支架能够做到这一点。在这项研究中，我们已经开发出具有选择性雌激素受体降解剂（SERD）和ER拮抗特性的新型支架。这些新颖的SERD可以有效抑制MCF-7乳腺癌细胞的增殖和ER靶基因的表达，其功效与Fulvestrant相当。与Fulvestrant不同的是，这些新型SERD的模块化蛋白靶向嵌合体（PROTAC）型设计应易于分散到类似物库中，以进一步微调其药代动力学特性，包括口服有效性。
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